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PubMed2003

Photoreaction, phototoxicity, and photocarcinogenicity of retinoids.

Sunlight is a human carcinogen. Many retinoid-containing cosmetics are used to protect damages caused by sunlight irradiation. Since retinol is thermally unstable and retinyl palmitate (RP) s relatively more stable, RP is also widely used as an ingredient in cosmetic formulations. In general, little is known about the photodecomposition of retinoids and the toxicity of retinoids and their photodecomposition products on the skin's responses to sunlight. This review focuses on the update information on photoreactions, phototoxicity, and photocarcinogenicity of the natural retinoids including retinol, retinal, retinoid acid (RA), retinyl acetate, and RP.

Animals↗
PubMed2006

Cyclic nucleotide-gated ion channels in rod photoreceptors are protected from retinoid inhibition.

In vertebrate rods, photoisomerization of the 11-cis retinal chromophore of rhodopsin to the all-trans conformation initiates a biochemical cascade that closes cGMP-gated channels and hyperpolarizes the cell. All-trans retinal is reduced to retinol and then removed to the pigment epithelium. The pigment epithelium supplies fresh 11-cis retinal to regenerate rhodopsin. The recent discovery that tens of nanomolar retinal inhibits cloned cGMP-gated channels at low [cGMP] raised the question of whether retinoid traffic across the plasma membrane of the rod might participate in the signaling of light. Native channels in excised patches from rods were very sensitive to retinoid inhibition. Perfusion of intact rods with exogenous 9- or 11-cis retinal closed cGMP-gated channels but required higher than expected concentrations. Channels reopened after perfusing the rod with cellular retinoid binding protein II. PDE activity, flash response kinetics, and relative sensitivity were unchanged, ruling out pharmacological activation of the phototransduction cascade. Bleaching of rhodopsin to create all-trans retinal and retinol inside the rod did not produce any measurable channel inhibition. Exposure of a bleached rod to 9- or 11-cis retinal did not elicit channel inhibition during the period of rhodopsin regeneration. Microspectrophotometric measurements showed that exogenous 9- or 11-cis retinal rapidly cross the plasma membrane of bleached rods and regenerate their rhodopsin. Although dark-adapted rods could also take up large quantities of 9-cis retinal, which they converted to retinol, the time course was slow. Apparently cGMP-gated channels in intact rods are protected from the inhibitory effects of retinoids that cross the plasma membrane by a large-capacity buffer. Opsin, with its chromophore binding pocket occupied (rhodopsin) or vacant, may be an important component. Exceptionally high retinoid levels, e.g., associated with some retinal degenerations, could overcome the buffer, however, and impair sensitivity or delay the recovery after exposure to bright light.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Enhancement of gap junctional communication by retinoids correlates with their ability to inhibit neoplastic transformation.

Retinoids that cause inhibition of methylcholanthrene-induced neoplastic transformation of C3H/10T1/2 cells enhance gap-junctional communication in carcinogen-initiated cells. Dose-response studies using retinoids of diverse structures and potency demonstrated a good correlation between these two events. Junctional permeability was enhanced by retinol and tetrahydrotetramethylnaphthalenyl propenylbenzoic acid (TTNPB) at concentrations from 10(-10) to 10(-6) M, and by retinoic acid between 10(-8) and 10(-6) M, the same concentrations that inhibited neoplastic transformation. Retinoic acid inhibited permeability at 10(-10) M, at which concentration transformation was enhanced. Retinoids caused similar alteration sin communication in parental 10T1/2 cells. Communication between initiated and 10T1/2 cells was not influenced by TTNPB. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibited junctional communication in initiated cells, in 10T1/2 cells and between these two cell lines. After repeated exposure of 10T1/2 cells to TPA only retinoid-enhanced communication was blocked; in contrast, basal communication became refractory. It is proposed that much of the chemopreventive action of retinoids can be explained by the enhanced junctional communication of growth regulatory signals.

Animals↗
PubMed2003

Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid.

We have reported previously that acyclic retinoid, a synthetic retinoid X receptor alpha (RXRalpha)-ligand, suppresses the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. On the other hand, HCCs become refractory to physiological concentrations of the natural RXRalpha-ligand, 9-cis retinoic acid (9cRA), due to extracellular signal-regulated kinase (Erk) 1/2-mediated phosphorylation and inactivation of RXRalpha. Here, we show that acyclic retinoid restores the function of RXRalpha in human HCC-derived HuH7 cells by inactivating the Ras-Erk 1/2 signaling system, thereby dephosphorylating RXRalpha. In contrast, 9cRA failed to suppress phosphoErk 1/2 levels and subsequent RXRalpha phosphorylation. Although 9cRA also suppressed Ras activity, it simultaneously down-regulated mitogen-activated protein kinase phosphatase-1, an enzyme that inactivates Erk, thereby leaving the phosphorylation status of Erk unchanged. A combination of 9cRA (a potent ligand) and acyclic retinoid (a weak ligand preventing phosphorylation) resulted in a marked cooperation in transactivation via the RXR-response element and in inhibiting the proliferation of HuH7 cells. These events provide a novel molecular basis for the antitumor activity of acyclic retinoid against HCC.

Antineoplastic Agents↗
PubMed1984

Structure-activity relationships of retinoids in the morphogenesis of cutaneous appendages in the chick embryo.

We have evaluated the efficacy of 13 analogues of retinoic acid (retinoids) in producing in vivo feathers on the normally scaly foot integument (ptilopody) of the chick embryo. The retinoids were dissolved in dimethylsulfoxide and injected at doses from 1.25-250 micrograms into the amniotic cavity of embryos of 10 days of incubation. The results showed that the production of ptilopody requires specific retinoids, namely, those incorporating a free trans carboxylic end group. Indeed, the esterification of this acid end group (retinoid ethyl ester) leads to a delay in the effect of the product. Its substitution by an alcohol (retinol) or an aldehyde group (retinal), or its isomerization, leads to inactive products. The esterification by acetic acid of the alcohol terminal group of retinol leads to a moderately active compound (retinyl acetate). By contrast, modifications of the ring do not interfere with the efficacy of the retinoid, and modifications of the side chain by addition of one or two supplementary rings lead to an increase of the activity.

Animals↗
PubMed1989

Synthetic retinoids inhibit the antigen presenting properties of epidermal cells in vitro.

The clinical efficacy of retinoids in benign and malignant skin diseases involving immune mechanisms suggests that they affect the immunologic functions of the epidermis. However, these effects have yet to be demonstrated. The action of vitamin A (retinol) and the synthetic retinoids, isotretinoin, etretinate, acitretin, and arotinoid-free acid have been studied on the lymphocyte proliferation induced by phytohemagglutinin (PHA), by the mixed lymphocyte reaction (MLR), and the mixed epidermal cell-lymphocyte reaction (MECLR). The results for PHA-induced proliferations were highly variable for all the retinoids. However, in MECLR, the synthetic retinoids consistently reduced the proliferation by 20%-30%. This occurred at therapeutic drug concentrations of about 10(-7)M. In MLR, a minor decrease of 10%-15% was only found for higher concentrations (10(-5)M). Retinol induced no effect in either reaction. Further analysis of acitretin on MECLR showed that it reduced lymphocyte proliferation in a dose-dependent fashion. This reduction was combined with a decrease in cytotoxic T-lymphocyte induction (CTL). Addition of 10(-6)M acitretin at various times also revealed that its presence at cell culture initiation was necessary to inhibit proliferation significantly. Furthermore, cell treatments prior to MECLR showed that exposure of epidermal cells to acitretin was essential to produce this inhibition, suggesting that it acts directly on epidermal cells. Consequently, it is suggested that the specific inhibitory effect of synthetic retinoids on lymphocyte activation in MECLR may partly account for their therapeutic action on the skin.

Acitretin↗
PubMed1990

Percutaneous retinoid absorption and embryotoxicity.

A single application of 17 micrograms/kg or 8.7 mg/kg all-trans-[10,11-3H2]-retinoic acid dissolved in acetone to shaved dorsal hamster skin resulted in rapid absorption and dose-dependent rates of elimination. An equation describing a two-compartment open model with a very brief lag time and first-order uptake and elimination was used to describe the central plasma compartment kinetics. Unchanged all-trans-retinoic acid represented less than or equal to 4% of the total circulating radio-activity. Peak circulating concentrations of parent all-trans-retinoic acid were less than those observed after an equivalent oral dose, but prolonged absorption from the skin appears to contribute to high total bioavailability of topical retinoid. Topical administration to intact skin of up to three consecutive doses of 10.5 mg/kg/d all-trans-retinoic acid or a single 5 mg/kg dose of etretinate (Ro 10-9359) during a critical stage of embryogenesis in hamsters caused erythema and/or dose-dependent epidermal hyperplasia at the site of application, but failed to induce a significant teratogenic response. Topical application of 0.01-1.0 mg/kg arotinoid Ro 13-6298 resulted in dose-dependent mucocutaneous toxicity and an increase in the numbers of dead embryos and malformed offspring. The marked skin toxicity and attenuated concentrations in maternal blood, compared to the oral route, limit the amounts of retinoid that can reach the hamster embryo. It is thus more important to compare the retinoid systemic values (absorbed dose) than it is to compare the oral or topical (applied) dose, when interpreting the results of conventional teratogenicity bioassays. The data suggest that in the human it is skin toxicity that limits the amounts of retinoid that can be applied and subsequently reach the embryo. In the rodent, overt skin toxicity under continued dosing could increase the amounts of retinoid penetrating the skin and reaching the embryo.

Administration, Oral↗
PubMed1995

Retinoic acid receptor gamma mediates topical retinoid efficacy and irritation in animal models.

Among retinoic acid receptors (RARs) alpha, beta, and gamma, the messenger RNA level of RAR-gamma is the most readily detectable by Northern blotting in human and mouse skin. This observation suggests that RAR-gamma may play a critical role in the modulation of the therapeutic benefits and side effects of retinoids in skin. To test this hypothesis, 11 RAR-gamma selective retinoids were synthesized based on three related structures. Each compound was found to prefer RAR-gamma when assessed by retinoid-induced transcriptional activity (RAR-gamma > RAR-beta > RAR-alpha). The apparent Kd for binding to recombinant receptor protein was found to follow a similar trend. To correlate this receptor selectivity with in vivo activity, the compounds were tested topically in the Rhino mouse utriculi reduction and rabbit irritation models, two assays widely used to screen retinoids for efficacy and side effects, respectively. The results indicated that for these compounds, both efficacy in the utriculi reduction assay and irritation potential in rabbits correlated positively with the RAR-gamma transactivation activity, with r2 of 0.9 and 0.8, respectively. These data suggest that RAR-gamma is an important regulator of retinoic acid efficacy in skin and further, that the irritation associated with the use of retinoids is most likely a receptor-mediated process.

Animals↗
PubMed1984

Animal assays for anti-psoriatic, retinoid and sun protective agents.

It is possible to evaluate different dermatological therapeutic agents intended for human use in a variety of animal assays. This review will discuss some of these assays, and attempt to correlate animal and human skin responses. Psoriasis is a disease where changes in epidermal proliferation may be an important factor. It is possible to assay potential anti-psoriatic agents by measuring their ability to suppress DNA synthesis in the epidermis of hairless mice. This assay is predictive of the anti-psoriatic effectiveness of numerous agents including a variety of anti-proliferative drugs and anthralin, and has been used to evaluate the potential efficacy of purified coal tar shampoos and body preparations. The activity of the polyamine biosynthesis enzyme ornithine decarboxylase (ODC) is elevated in psoriatic skin, and it is induced in mouse epidermis by tape stripping. Retinoids can inhibit the induction of ODC activity, and this inhibition may be used to evaluate novel synthetic retinoids. Retinoids have beneficial effects on the abnormal keratinization found in various diseases. Rhino mice have multiple keratin-filled epidermal utricles, and the size of these is reduced by retinoid treatment. Observing the changes in the size of the utricles can be utilized to evaluate the effects of retinoids on keratinization. Sunscreen agents are tested on human volunteers by observing their ability to inhibit the erythema induced by exposure to solar-simulated light, to obtain a sun protection factor (SPF). It is possible to utilize the ability of sunscreens to inhibit other actinic-induced changes in the skin using animals. Parameters that may be measured include changes in DNA synthesis and ODC activity in the epidermis following ultraviolet irradiation. Some of these assays correlate well with human SPF determinations.

Adolescent↗
PubMed1992

Retinoid augmentation of bioactive interleukin-1 production by murine keratinocytes.

The effect of retinoids on the production of interleukin-1 (IL-1) by murine epidermal keratinocytes was investigated. Freshly isolated keratinocytes were cultured in the presence of etretinate, acitretin, all-trans retinoic acid or 13-cis retinoic acid at concentrations of 8 x 10(-9)-8 x 10(-6) mol/l. Exposure of keratinocytes to retinoids increased IL-1 bioactivity in culture supernatants and cell extracts at concentrations as low as 8 x 10(-9) mol/l, as assessed by T-cell proliferation. Prolongation of the culture period enhanced the augmentative effect of retinoids. All-trans retinoic acid and 13-cis retinoic acid had a greater ability to induce IL-1 production than the two aromatic retinoids, etretinate and acitretin. Treatment with 8-methoxypsoralen plus ultraviolet A radiation and treatment with triamcinolone acetonide both reduced the effect of retinoids on the production of bioactive IL-1.

Acitretin↗
PubMed1985

Retinoids alter the direction of differentiation in primary cultures of cutaneous keratinocytes.

The effects of vitamin A on the morphological expression of differentiation were studied in cell cultures of cutaneous keratinocytes from the newborn rat. The cells were first cultivated in a medium containing 0.11 mM calcium until a confluent monolayer had been formed. Stratification and terminal differentiation were then triggered by raising the calcium concentration of the medium to 1.96 mM ('normal' culture). The rise in the concentration of calcium was coupled with the addition of retinol (RL) of retinoic acid (RAC) to the medium to produce an excess of vitamin A (high-retinoid culture). Delipidized serum was used to produce a deficiency of vitamin A (low-retinoid culture). The tissue organization and the ultrastructure of the keratinocytes in the stratified culture were the same as those seen in conventional cultures and skin explants. These stratified cultures expressed the morphological features of the epidermis of intact skin. The addition of RL or RAC to the medium enhanced features characteristic of the secretory epithelium, such as the formation of an extensive endoplasmic reticulum, an enlargement of the Golgi zone, and an increase in the number of vacuoles. At the same time, the addition of retinoids diminished features characteristic of the terminal differentiation of the stratified squamous epithelium, such as stratification and keratinization. Deficiency of vitamin A in the medium resulted in a culture with many differentiated layers. The differentiated cells of the low-retinoid cultures contained densely packed tonofilaments and synthesized products that reacted with the monoclonal antibody AE2 that is specific for keratin peptides which are markers of epidermal differentiation. In the cell culture system that is presented here, an excess of retinoids redirected epithelial differentiation from a stratifying and keratinizing epithelium towards a secretory epithelium. This system is a useful tool for elucidating the mechanisms responsible for the effect of vitamin A on the differentiation of epithelial cells.

Animals↗
PubMed1993

Retinoid-dependent transcriptional suppression of cytokeratin gene expression in human epidermal squamous cell carcinoma cells.

We have previously demonstrated that cytokeratin levels are coordinately regulated in normal cultured human keratinocytes. In the present study we examine the mechanism of this regulation using human squamous cell carcinoma (SCC) cells. Treatment of SCC-13 cells with 20 or 200 nM trans-retinoic acid results in nearly complete suppression of cytokeratin K5 and K6 expression. This change is accompanied by a simultaneous reduction (> 20-fold) in the level of the mRNAs encoding K5 and K6. Transcriptional analysis indicates that the transcription rate of the K5 and K6 genes drops by approximately four to fivefold in retinoid treated nuclei. Retinol (2000 nM) also promotes this change. In contrast, cytokeratin K19 does not increase in the presence of retinoic acid, thus the normal coordinate regulation of keratin gene expression by retinoids appears to be uncoupled in SCC-13 cells. However, this does not represent a general defect in positive regulation of gene expression by retinoids, since in a transient transfection assay trans-retinoic acid positively regulates a reporter plasmid containing the retinoid response element from the retinoic acid receptor-beta gene. The synthetic retinoids Ro 13-6298 (ethyl ester) and its metabolic derivative Ro 13-7410 (free acid) are both active in modulating the differentiation of normal keratinocytes. In contrast, only Ro 13-7410 is active in SCC-13 cells. As Ro 13-6298 binds poorly to the retinoic acid receptors, this suggests that SCC-13 cells, unlike normal keratinocytes, lack the ability to convert Ro 13-6298 to the active Ro 13-7410.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMedDate not supplied

Retinoid therapy of pigmentary disorders.

Topical retinoids such as all-trans-retinoic acid (RA), 13-cis-retinoic acid (isotretinoin), retinol, retinaldehyde, tazarotene, and adapalene have been shown to improve dyspigmentation of photodamaged skin including mottling and actinic lentigines. RA monotherapy has also been demonstrated to improve melasma and postinflammatory hypermelanosis. Furthermore, RA in combination with hydroquinone or 4-hydroxyanisole, or azelaic acid increases the potency of depigmenting agents for the treatment of melasma, actinic lentigines, and postinflammatory hypermelanosis. The basic mechanisms underlying these effects are not completely identified. Topical retinoids stimulate the cell turn-over of epidermal keratinocytes and promote a decrease in melanosome transfer and a rapid loss of melanins via epidermopoiesis. Topical retinoids are also involved in the control of cell differentiation. Retinoid-induced changes in the stratum corneum and the permeability barrier may also facilitate the penetration of depigmenting agents in the epidermis and increase their bioavailability, leading to increased depigmentation. In addition, several in vitro studies demonstrate that cis and trans-retinoic acid inhibit UV-B stimulated melanogenesis in term of tyrosinase activity and melanin synthesis. It is likely that topical retinoids modulate epidermal melanin count via a direct action on melanocytes and epidermal keratinocytes.

Humans↗
PubMed1998

Retinoid teratogenicity in the macaque: verification of dosing regimen.

To further define teratogenicity associated with 13-cis-retinoic acid (13-cis-RA) in the cynomolgus monkey, the drug was orally administered on three different treatment regimens. Experiment (Exp.) 1 (2.5 mg/kg/day, gestational day [GD] 12-27, n = 11) investigated the teratogenicity of a single daily dose of 13-cis-RA administered shortly after embryo implantation. Pharmacokinetic sampling was done to determine retinoid profiles on the first (GD12) and last (GD27) days of treatment. Exposure to 13-cis-RA during early organogenesis in Exp. 2 (2.5 mg/kg/day, GD20-27, and 2 x 2.5 mg/kg/day, GD28-30, n = 5) investigated the potential adverse effects of 13-cis-RA on the developing limb. The use of multiple doses of 13-cis-RA in Exp. 3 (2 x 2.5 mg/kg/day, GD26-27, n = 5) investigated the necessity of double dosing on the induction of retinoid embryopathy in the macaque. Malformations of retinoid target organs as well as embryolethality were most prevalent when single daily doses of 13-cis-RA were administered during pre- and early organogenesis in Exp. 1. Moreover, multiple doses on GD26-27 failed to induce any manifestation of abnormal development in Exp. 3. These results confirm that the lowest observed adverse effect level (LOAEL) in macaques is 2.5 rather than 5.0 times greater than that observed in human pregnancies. Exposure during forelimb development (GD20-30) in Exp. 2 was unsuccessful in inducing defects of this skeletal region, although defects in several retinoid target organs (i.e., cerebellum and internal ear) were present, indicating that a teratogenic threshold was achieved. Pharmacokinetic analysis of 13-cis-RA and its metabolites on GD12 and 27 in Exp. 1 showed considerable exposure to the administered drug and its 4-oxo-metabolite. In contrast, the exposure to all-trans-RA was negligible. The results support the use of a specific treatment schedule in early gestation in the macaque as the most appropriate model for characterizing the teratogenic potential of retinoids in humans.

Abnormalities, Drug-Induced↗
PubMed2002

Unique property of some synthetic retinoids: activation of the aryl hydrocarbon receptor pathway.

Potential pharmacological applications in the areas of oncology, dermatology, diabetes, and atherosclerosis of synthetic analogs of retinoic acid that target a specific nuclear receptor and/or biological response have generated great interest in the development of new retinoid and rexinoid drugs. The pan-retinoic acid receptor antagonist AGN 193109 has been previously reported to elevate CYP1A1 levels, implicating the aryl hydrocarbon receptor (AhR) as an additional target for this retinoid. AhR is a cytosolic ligand-dependent transcription factor that, in conjunction with the AhR nuclear translocator (Arnt), binds to dioxin response elements (DREs) located in the promoter region of target genes, such as CYP1A1, and induces their transcription. The purpose of these studies was to determine whether additional synthetic retinoids were capable of elevating CYP1A1 levels and to examine the mechanism of this increase in CYP1A. Two additional retinoids, AGN 190730 and AGN 192837, were found to be potent inducers of DRE-driven transcriptional activity; AGN 190730 was the most potent. Moreover, electrophoretic mobility-shift assays demonstrate that AGN 190730 can transform AhR into its active DNA recognition form. In addition, trypsin digestion of AGN 190730-treated AhR reveals a conformational change in the protein similar to the conformational change of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-bound AhR. Finally, competitive binding studies demonstrate that AGN 190730 can inhibit the binding of TCDD to AhR. The sum of the data demonstrates that some synthetic retinoids in addition to activating the retinoic acid receptor/retinoid X receptor pathway are capable of binding to AhR and activating the AhR/Arnt pathway.

Adamantane↗
PubMed2003

Differential regulation of nonsteroidal anti-inflammatory drug-activated gene in normal human tracheobronchial epithelial and lung carcinoma cells by retinoids.

In this study, we analyze the effect of several retinoids on the expression of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in normal human tracheobronchial epithelial (HTBE) cells and several lung carcinoma cell lines. The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) greatly enhances the expression of NAG-1 mRNA and protein in a time- and dose-dependent manner in human lung adenocarcinoma H460 cells and several other carcinoma cell lines. This induction was specific for AHPN because retinoic acid, a retinoic acid receptor-, and a retinoid X receptor pan-agonist were unable to induce NAG-1, suggesting that this induction is not mediated through activation of retinoid receptors. Although NAG-1 is a p53-responsive gene, AHPN-induced NAG-1 expression does not require p53. The induction of NAG-1 expression by AHPN is caused at least in part by an 8-fold increase in the stability of NAG-1 mRNA. In contrast to carcinoma cells, NAG-1 expression is effectively induced by retinoic acid and the RAR-selective pan-agonist in normal HTBE cells and accompanies the inhibition of squamous differentiation and the initiation of normal differentiation. In vivo, NAG-1 expression was observed in the normal tracheobronchial epithelium, whereas no expression was found in either squamous metaplastic tracheal epithelium or in sections of human lung tumors. Our results suggest that the induction of NAG-1 expression by retinoids in normal HTBE and lung carcinoma cells is regulated by distinct mechanisms and is associated with different biological processes. The linkage between AHPN treatment and NAG-1 expression revealed in this study provides a new mechanism for the antitumorigenic activity of AHPN.

Adenocarcinoma↗
PubMed2006

TGIF inhibits retinoid signaling.

TGIF (TG-interacting factor) represses transforming growth factor beta (TGF-beta)-activated gene expression and can repress transcription via a specific retinoid response element. Mutations in human TGIF are associated with holoprosencephaly, a severe defect of craniofacial development with both genetic and environmental causes. Both TGF-beta and retinoic acid signaling are implicated in craniofacial development. Here, we analyze the role of TGIF in regulating retinoid responsive gene expression. We demonstrate that TGIF interacts with the ligand binding domain of the RXRalpha retinoid receptor and represses transcription from retinoid response elements. TGIF recruits the general corepressor, CtBP, to RXRalpha, and this recruitment is required for full repression by TGIF. Interaction between TGIF and RXRalpha is reduced by the addition of retinoic acid, consistent with a role for TGIF as an RXRalpha transcriptional corepressor. We created a Tgif null mutation in mice and tested the sensitivity of mutant mice to increased levels of retinoic acid. Tgif mutant embryos are more sensitive to retinoic acid-induced teratogenesis, and retinoid target genes are expressed at a higher level in tissues from Tgif null mice. These results demonstrate an important role for TGIF as a transcriptional corepressor, which regulates developmental signaling by retinoic acid, and raises the possibility that TGIF may repress other RXR-dependent transcriptional responses.

Animals↗
PubMed1996

Quantitation of mucin RNA by PCR reveals induction of both MUC2 and MUC5AC mRNA levels by retinoids.

The polydispersity of most human secretory mucin messages has made them difficult to detect specifically and quantitatively, impeding the evaluation of the relative expression of the various mucin genes and their role in normal and pathological conditions. For this reason, we developed competitive reverse transcriptase-polymerase chain reaction (PCR) methods to measure the airway mucins MUC2 and MUC5AC. Oligonucleotide pairs were designed that specifically detect MUC2 and MUC5AC, as demonstrated by the size and sequence of the PCR product and the expected tissue distribution. The mucin oligonucleotide primers were used to synthesize internal competitive standards, called MIMIC. Using this assay, the relative expression of these messages was analyzed in retinoid-replete or -deprived cultures of normal human tracheobronchial epithelial (NHTBE) cells. Retinoid deficiency induces squamous metaplasia in vivo and in vitro. Consistent with these observations and in contrast to a previous report, retinoid-deprived cultures produced at least an order of magnitude less MUC2 and MUC5AC message than retinoid-replete cultures. In summary, this paper describes methodology that can be applied to the specific and quantitative measurement of mucin messages and demonstrates that, in NHTBE cells, the level of MUC2 and MUC5AC mRNA is increased by retinoids.

Cell Line↗